Apparatus and methods for detecting optical signals from implanted sensors

ABSTRACT

Some embodiments described herein relate to an apparatus including a light source configured to transmit an excitation optical signal to an implanted sensor and a detector configured to detect an analyte-dependent optical signal emitted from an implanted sensor. The apparatus can include a lens configured to focus at least a portion of the analyte-dependent optical signal onto the detector.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to provisionalU.S. patent application No. 61/832,065, entitled “Detection of ImplantOptical Signals with Off-Axis Light Restriction,” and to provisionalU.S. patent application No. 61/832,078, entitled “Detection of ImplantOptical Signals with Large Ratio of Surface Area,” each filed Jun. 6,2013, the disclosure of each of which is incorporated herein byreference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant number NIHR01 EB016414 and NIH R43 DK093139, awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND

Some embodiments described herein relate to apparatus and methods formonitoring an implant, and in particular to apparatus and methods fordetecting optical signals emitted from an implant with restriction ofoff-axis light.

Some embodiments described herein relate to apparatus and methods formonitoring an implant, and in particular to apparatus and methods fordetecting optical signals through a relatively large surface area oftissue relative to a surface area of tissue through which an excitationoptical signal is supplied.

The monitoring of the level or concentration of an analyte, such asglucose, lactate, oxygen, etc., in certain individuals is important totheir health. High or low levels of glucose, or other analytes, may havedetrimental effects or be indicative of specific health states. Themonitoring of glucose is particularly important to persons withdiabetes, a subset of whom must determine when insulin is needed toreduce glucose levels in their bodies or when additional glucose isneeded to raise the level of glucose in their bodies.

A conventional technique used by many persons with diabetes formonitoring their blood glucose level includes the periodic drawing ofblood, the application of that blood to a test strip, and thedetermination of the blood glucose level using calorimetric,electrochemical, or photometric detection. This technique does notpermit continuous or automatic monitoring of glucose levels in the body,but typically must be performed manually on a periodic basis.Unfortunately, the consistency with which the level of glucose ischecked varies widely among individuals. Many persons with diabetes findthe periodic testing inconvenient, and they sometimes forget to testtheir glucose level or do not have time for a proper test. In addition,some individuals wish to avoid the pain associated with the test.Unmonitored glucose may result in hyperglycemic or hypoglycemicepisodes. An implanted sensor that monitors the individual's analytelevels would enable individuals to monitor their glucose, or otheranalyte levels, more easily.

Some known devices perform in situ monitoring of analytes (e.g.,glucose) in the blood stream or interstitial fluid of various tissues. Anumber of these devices use sensors that are inserted into a bloodvessel or under the skin of a patient. Communicating and/or retrievingdata from such known and/or proposed devices, however, can bechallenging. For example, an implanted sensor may be able to communicatewith a detector or receiver using radio frequency (RF) transmissions.Such a sensor, however, may require electronics, batteries, antennae,and/or other communication hardware which may increase the bulk of theimplanted sensor, may require frequent inconvenient recharging, and/ormay decrease the longevity or reliability of the implant.

A need therefore exists for apparatus and methods for detecting opticalsignals from an implanted sensor, such that a fluorescent sensor can beused. A fluorescent sensor may not require electric charging and/ortransmission electronics. Such implanted sensors, however, may bedifficult to read or to monitor optically because of low levels offlorescence in the presence of high scatter due to dynamic changes inskin conditions (e.g., blood level and hydration). The skin is highlyscattering, and the scattering may dominate the optical propagation.Scatter is caused by index of refraction changes in the tissue, and themain components of scatter in the skin are due to lipids, collagen, andother biological components. The main absorption is caused by blood,melanin, water, and other components.

Devices and apparatus described herein are suitable for providingaccurate and consistent measurement of an analyte by monitoring animplantable sensor in such low-signal, high-scattering environments.

SUMMARY

Some embodiments described herein relate to an apparatus including alight source configured to transmit an excitation optical signal to animplanted sensor and a detector configured to detect ananalyte-dependent optical signal emitted from an implanted sensor. Theapparatus can include a lens configured to focus at least a portion ofthe analyte-dependent optical signal onto the detector.

Some embodiments described herein relate to an array of lenses. Eachlens from the array of lenses can be configured to transmit ananalyte-dependent optical signal from an implanted sensor to a detector.A plurality of light-blocking elements can be disposed within asubstrate of the array of lenses. Each light blocking element from thearray of light-blocking elements can be configured to prevent or inhibita photon having an angle of incidence greater than a predetermined angleof incidence from passing through the substrate.

Some embodiments described herein relate to an apparatus including adetector configured to detect an analyte-dependent optical signal froman implanted sensor. A lens can be configured to focus at least aportion of the analyte-dependent optical signal onto the detector. Afilter can be configured to attenuate light having wavelengths shorterthan the analyte-dependent optical signal.

Some embodiments described herein relate to an implant capable ofemitting, in response to excitation light in at least one excitationwavelength range, at least one analyte-dependent optical signal in atleast one emission wavelength range. A device including at least onelight source can be arranged to transmit the excitation light throughtissue surrounding the implant. The device can include at least onedetector arranged to detect light emitted from implanted sensor andtransmitted through the tissue in the emission wavelength range. Thedevice can also include an array of lenses arranged with an array ofapertures to restrict transmission of off-axis light to the detector.The arrays of lenses and the array of apertures can be positioned withrespect to the detector to restrict the light emitted from the tissuethat travels to the detector based on the incidence angle of the emittedlight. At least one layer of light control film can be arranged with thelens and aperture arrays to restrict the light emitted from the tissuethat travels to the detector based on the incidence angle of the emittedlight relative to the film. The device can further include at least onefilter positioned to restrict transmission of light to the detector towavelengths substantially within the emission wavelength range.

Some embodiments described herein relate to an optical detection deviceis for monitoring an implant embedded in tissue of a mammalian body. Theimplant is capable of emitting, in response to excitation light in atleast one excitation wavelength range, at least one analyte-dependentoptical signal in at least one emission wavelength range. The device caninclude at least one light source arranged to transmit the excitationlight through the tissue to the implant. At least one detector isarranged to detect light emitted from the tissue in the emissionwavelength range. The device can also include an array of lensesarranged with an array of apertures to restrict transmission of off-axislight to the detector. The arrays of lenses and the array of aperturesare positioned with respect to the detector to restrict the lightemitted from the tissue that travels to the detector according to aninput angle of the emitted light. Light-blocking elements are arrangedbetween the apertures to block propagation of incident light raysthrough the apertures. The light-blocking elements are positioned toblock the incident light rays in accordance with an increase in incidentangle of the light rays with respect to optical axes of the apertures.The device further comprises at least one filter arranged to restrictthe transmission of the emitted light to the detector to wavelengthssubstantially within the emission wavelength range.

Some embodiments described herein relate to a method for monitoring animplant embedded in tissue of a mammalian body. The implant is capableof emitting, in response to excitation light in at least one excitationwavelength range, at least one analyte-dependent optical signal in atleast one emission wavelength range. The method can include transmittingthe excitation light through the tissue to the implant and detectinglight emitted from the tissue in the emission wavelength range. Thelight in the emission wavelength range is transmitted through an arrayof lenses and an array of apertures arranged to restrict the lightemitted from the tissue that travels to at least one detector accordingto an input angle of the emitted light. The light in the emissionwavelength range is also transmitted through at least one layer of lightcontrol film arranged with the lens and aperture arrays to restrict thelight emitted from the tissue that travels to the detector according toan incident angle of the emitted light relative to the film. The lightin the emission wavelength range is also transmitted through at leastone filter positioned to restrict transmission of light to the detectorto wavelengths substantially within the emission wavelength range.

Some embodiments described herein relate to a method for monitoring animplant embedded in tissue of a mammalian body. The implant is capableof emitting, in response to excitation light in at least one excitationwavelength range, at least one analyte-dependent optical signal in atleast one emission wavelength range. The method can include transmittingthe excitation light through the tissue to the implant and detectinglight emitted from the tissue in the emission wavelength range. An arrayof apertures arranged with an array of lenses restricts the lightemitted from the tissue that travels to at least one detector accordingto an input angle of the emitted light. The method can also includeblocking propagation of incident light rays through the apertures usinglight-blocking elements positioned between the apertures to block theincident light rays having an angle of incidence greater than athreshold angle of incidence based on, for example, the optical axes ofthe apertures. The method can further include filtering the emittedlight to wavelengths substantially within the emission wavelength range.

Some embodiments described herein relate to an optical detection devicefor monitoring an implant embedded in tissue under skin. The implant iscapable of emitting, in response to excitation light in at least oneexcitation wavelength range, at least one analyte-dependent opticalsignal in at least one emission wavelength range. The device can includeat least one light source arranged to transmit the excitation lightthrough a first surface area of the skin to the implant embedded in thetissue. One or more detectors can be arranged to detect light that isemitted from at least a second surface area of the skin, wherein thelight source and one or more detectors are arranged such that the ratioof the surface area of the skin through which the detected light passesas it travels to the one or more detectors to the surface area of theskin through which the excitation light is transmitted is at least 4:1.

Some embodiments described herein relate to a method for monitoring animplant embedded in tissue under skin. The implant can be capable ofemitting, in response to excitation light in at least one excitationwavelength range, at least one analyte-dependent optical signal in atleast one emission wavelength range. The method can include transmittingthe excitation light through a first surface area of the skin to theimplant embedded in the tissue and detecting light that is emitted fromat least a second surface area of the skin. The ratio of the surfacearea of the skin through which the detected light passes as it travelsto one or more detectors to the surface area of the skin through whichthe excitation light is transmitted is at least 4:1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view of an optical detection device formonitoring an implant, according to an embodiment.

FIG. 2 is a schematic side view of an optical detection device formonitoring an implant, according to an embodiment.

FIG. 3 is a plan view of an aperture array, according to an embodiment.

FIG. 4 is a schematic plan view of an optical detection device,according to an embodiment.

FIG. 5 is a schematic exploded view of an optical detection device,according to an embodiment.

FIG. 6 is a schematic side view of an optical detection device formonitoring an implant, according to an embodiment.

FIG. 7 is a schematic side view of an optical detection device formonitoring an implant, according to an embodiment.

FIGS. 8A-8D depict a lens and aperture array with light-blockingelements in various stages of fabrication, according to an embodiment.

FIG. 9 is a schematic plan view of an optical detection device,according to an embodiment.

FIG. 10 is a schematic plan view of an optical detection device,according to an embodiment.

FIG. 11 is a schematic plan view of an optical detection device,according to an embodiment.

DETAILED DESCRIPTION

According to some embodiments described herein, an optical detectiondevice is provided for monitoring an implant embedded in tissue of amammalian body. The implant can include a fluorophore-labeled targetcapable of emitting, in response to excitation light in at least oneexcitation wavelength range, at least one analyte-dependent opticalsignal in at least one emission wavelength range. The optical detectiondevice can be operable to illuminate the implant with light whosewavelength content falls within an absorption band and/or collect lightwhose wavelength content is in an emission band.

The optical detection device can include excitation optics including alight source and/or optics operable to generate illumination in theabsorption band. The optical detection device can also include emissionoptics operable to collect fluorescent emissions from the implant.Because in some instances, it may be difficult to obtain, design, and/orimplement a light source that has a spectral content (i.e., wavelengthrange) that exactly matches every fluorophore absorption band, anoptical filter or filters (usually band-pass filters) can be used alongwith the light source to limit the range of illuminating wavelengths tothat of the absorption band and/or to reduce illuminating wavelengths ofthe emission band. Similarly, the emission optics can include anotherfilter or filters operable to allow substantially only light withwavelengths in the emission band to reach the detector and/or toattenuate light with other wavelengths (e.g., light in the absorptionband). Similarly stated, the optical detection device can include anoptical system design operable to allow substantially only photons withwavelengths in the absorption band reach the target, and substantiallyonly photons with wavelengths in the emission band reach the detector.Without proper optics, photons from the light source may be reach thedetector and induce a measurement error.

Properly designing an optical system for an optical detection device canbe complicated in instances in which the amount of emitted fluorescenceto be detected is much less than the amount of excitation lightscattered (e.g., not absorbed) by an intermediate surface (e.g., skin ortissue disposed between the optical detection device and the implant).One challenge is that the amount of excitation light that reaches theimplant may be low because of the absorption and scattering caused bythe various body parts (skin, tissue, etc.). The low amount of emittedfluorescence is further reduced by absorption and scattering as it makesits way out of the body towards the detector. Existing optical filtertechnology, which may provide rejection of unwanted photons on the orderof (10⁻⁶) may be insufficient in these situations. Another challenge isthat the difference between excitation and detection wavelengths (e.g.,Stokes shift) may be quite small. A further challenge is that dichroicfilters cause shifting (e.g., the “blue shift”) of filter wavelengths asa function of the angle of light rays transmitted through the filter.Because of these challenges, standard fluorescence methods would allowthrough high background levels and, in turn, result in lowSignal-to-Background (SBR) and Signal-to-Noise (SNR) ratios.

Some embodiments described herein relate to a compact device that canaccurately and consistently monitor an implanted sensor. Such a devicecan be worn by a user substantially continuously and/or may notsubstantially restrict movements or activities of the user. The deviceand the sensor can collectively allow for continuous and/or automaticmonitoring of an analyte and can provide a warning to the person whenthe level of the analyte is at or near a threshold level. For example,if glucose is the analyte, then the monitoring device might beconfigured to warn the person of current or impending hyperglycemia orhypoglycemia. The person can then take appropriate actions.

In the description contained herein, it is understood that all recitedconnections between structures can be direct operative connections orindirect operative connections through intermediary structures. A set ofelements includes one or more elements. Any recitation of an element isunderstood to refer to at least one element. A plurality of elementsincludes at least two elements. Unless clearly indicated otherwise, anydescribed method steps need not be necessarily performed in a particularor illustrated order. A first element (e.g. data) derived from a secondelement encompasses a first element equal to the second element, as wellas a first element generated by processing the second element andoptionally other data. Making a determination or decision according to aparameter encompasses making the determination or decision according tothe parameter and optionally according to other data. Unless otherwisespecified, an indicator of some quantity/data may be the quantity/dataitself, or an indicator different from the quantity/data itself. Someembodiments described herein reference a wavelength, such as anexcitation wavelength or an emission wavelength. Unless clearlyindicated otherwise, a wavelength should be understood as describing aband of wavelengths including the wavelength. Computer programsdescribed in some embodiments of the present invention may bestand-alone software entities or sub-entities (e.g., subroutines, codeobjects) of other computer programs. Computer readable media encompassnon-transitory media such as magnetic, optic, and semiconductor storagemedia (e.g. hard drives, optical disks, flash memory, DRAM), as well ascommunications links such as conductive cables and fiber optic links.According to some embodiments, the present invention provides, interalia, computer systems comprising hardware (e.g. one or more processorsand associated memory) programmed to perform the methods describedherein, as well as computer-readable media encoding instructions toperform the methods described herein.

The following description illustrates embodiments of the invention byway of example and not necessarily by way of limitation.

FIG. 1 is a schematic side view of an optical detection device 10 formonitoring an implanted sensor or implant 12, according to anembodiment. The implant 12 is embedded in tissue 15 of a mammalian body(which may be a piece of tissue that is attached or unattached to therest of the body in various embodiments). The implant 12 can be embeddedunder a surface of skin 14. The implant 12 can be embedded and/orpositioned in the subcutaneous tissue (e.g., in the range of 1 to 4 mmunder the surface of the skin 14). The implant 12 is capable ofemitting, in response to excitation light within an excitationwavelength range, at least one analyte-dependent optical signal withinan emission wavelength range. The analyte may be, for example, glucoseor other analytes in the tissue 15. Suitable optical signals include,without limitation, luminescent, bioluminescent, phosphorescent,autoluminescence, and diffuse reflectance signals. In some embodiments,the implant 12 contains one or more luminescent dyes (e.g., fluorescentdyes) whose luminescence emission intensity varies in dependence uponthe amount or presence of target analyte in the body of the individual(e.g., in tissue 15).

A light source 18 is arranged to transmit excitation light within theexcitation wavelength range from the surface of the skin 14, through thetissue 15, and to the implant 12. Suitable light sources include,without limitation, lasers, semi-conductor lasers, light emitting diodes(LEDs), and organic LEDs. Detectors 16, 20 are arranged with the lightsource 18 to detect light emitted from the tissue in the emissionwavelength range. Suitable detectors include, without limitation,photodiodes, complementary metal-oxide-semiconductor (CMOS) detectors orcharge-coupled device (CCD) detectors. Although multiple detectors areshown, a single and/or universal detector can be used.

The detectors can be 16, 20 filtered (e.g., with dichroic filters orother suitable filters) to measure the optical signals emitted withinthe wavelength ranges. For example, a suitable luminescent dye sensitiveto glucose concentration is Alexa Flour® 647 responsive to excitationlight (absorption) in the range of about 600 to 650 nm (absorption peak647 nm) and within an emission wavelength range of about 670 to 750 nmwith an emission peak of about 680 nm. Thus, in an embodiment in whichthe sensor includes Alexa Flour® 647, the detectors 16, 20 can befiltered from light having a wavelength shorter than about 650 nm orshorter than about 670 nm.

In some embodiments, the implant 12 is further capable of emitting, inresponse to excitation light within a second excitation wavelengthrange, at least one analyte-independent optical signal within a secondemission wavelength range. For example, the implant 12 can contain ananalyte-independent luminescence dye that functions to control fornon-analyte physical or chemical effects on a reporter dye (e.g., photobleaching or pH). Multiple dyes may be used. The analyte-independentoptical signal is not modulated by analyte present in the tissue 15 andprovides data for normalization, offset corrections, or internalcalibration. The analyte-independent signal may compensate fornon-analyte affects that are chemical or physiological (e.g., oxygen,pH, redox conditions) or optical (e.g., water, lightabsorbing/scattering compounds, hemoglobin). Alternatively, theanalyte-independent signal may be provided by a stable reference dye inthe implant 12. Suitable stable reference materials include, but are notlimited to, lanthanide-doped crystals, lanthanide-doped nanoparticles,quantum dots, chelated lanthanide dyes, and metal (e.g., gold or silver)nanoparticles. The stable reference dye may provide a reference signalfor other signals (e.g., to determine photo bleaching).

In the operation of device 10, the light source 18 is activated totransmit excitation light within the excitation wavelength range fromthe surface of the skin 14, through the tissue 15, and to the implant12. The dye in the implant 12 absorbs some of the excitation light andemits fluorescence that depends on glucose or other analyte properties.The light may be emitted from the implant 12 in all directions, andscattered by the tissue 15. Some of the light that is emitted from theimplant 12 is transmitted through the tissue 15 and detected by at leastone of the detectors 16, 20. This can provide the primaryanalyte-dependent optical signal. In embodiments in which a referenceoptical signal is used for normalization, the light source 18 (or asecond light source) is activated to transmit second excitation lightfrom the surface of the skin 14 to the implant 12. At least one of thedetectors 16, 20 measures, in response to the second excitation light, asecond optical signal emitted from the tissue 15 through the surface ofthe skin 14.

The second optical signal may be used to normalize the primaryanalyte-dependent optical signal for scattering of light emitted fromthe implant 12. At least one corrected signal value may be calculated independence upon the measured optical signals. In one example, theprimary analyte-dependent signal from the implant may be normalized bythe analyte-independent optical signal emitted from the implant 12.Prior to executing optical reads for the analyte-dependent signal and/orthe analyte-independent signal, a dark reading may be taken to accountfor background or ambient light, and this reading may be used to furthercorrect the signals, e.g., by background subtraction.

In some embodiments, an analyte value (e.g., glucose concentration) isdetermined from the analyte-dependent signal and/or a ratio of multipleoptical signals including one or more reference signals. In one example,the signal from the glucose sensitive fluorophore (e.g., Alexa Flour®647) is normalized by the signal from a glucose insensitive fluorophore(e.g., Alexa Flour® 700). One suitable dye for the analyte-independentsignal is Alexa Flour® 750 which is responsive to excitation lightwithin an excitation wavelength range of about 700 to 760 nm (excitationpeak 750 nm) and has an emission wavelength range of about 770 to 850 nmwith an emission peak of about 780 nm.

An analyte value can be determined based on the optical signal(s) using,for example, a look-up table or calibration curve. Determining theanalyte value can be implemented in software (executing on a processor)and/or hardware. For example, the optical device 10 can include amicroprocessor. In some embodiments, the microprocessor is programmed tostore measured optical signal values in a memory and/or to calculatenormalized signal values and analyte concentrations. Alternatively,these functions may be performed in a separate processor or externalcomputer in communication with the optical device 10. The externalprocessor or computer can receive data representative of the measuredoptical signals and calculates the corrected signal value and analyteconcentration. Alternatively, multiple processors may be provided, e.g.,providing one or more processors in the optical device that communicate(wirelessly or with wires) with one or more external processors orcomputers.

In some embodiments in which two implant dyes (e.g., luminescent dyes)are utilized, it is possible that the implant dyes may share or overlapexcitation (absorption) or emission wavelength ranges. In one example,the emission wavelength range of the first dye, which provides theanalyte-dependent luminescence signal, shares or overlaps the excitationwavelength range of the second dye, which provides theanalyte-independent luminescence signal. In another embodiment, thefirst and second dyes may share or overlap excitation wavelength ranges(so that a common light source may be used) and emit optical signalswithin different emission wavelength ranges. In another embodiment, thefirst and second dyes may be excited by light within differentexcitation wavelength ranges and emit optical signals within the same oroverlapping emission wavelength range(s).

The implant 12 can be embedded in subcutaneous tissue (e.g., 1 to 4 mmunder the surface of the skin 14). In some embodiments, the implant 12comprises hydrogel scaffolds embedded with glucose-sensing nanospheres.The design of the implant 12 can use injectable, tissue-integrating,vascularizing scaffolds as the sensor. Embedded nanospheres emitluminescence that changes intensity and lifetime in response to thepresence or concentration of the analyte (e.g., interstitial glucose).The spacing distances between each of the detectors 16, 20 and the lightsource 18 determine the depths of the respective light paths fordetecting optical signals from the implant 12. The combination of anexcitation light source and a detection band is an optical channel. Thelight source 18 and detectors 16, 20 can be arranged such that a surfacearea of skin 14 through which the excitation light is transmitted islocated between substantially surrounding surface areas of skin 14through which the detected light passes as it travels from the tissue 15to one or more detectors 16, 20.

Although only one light source 18 and two detectors 16, 20 are shown inFIG. 1, in some embodiments, the optical device 10 can have any numberof light sources and any number of detectors. The optical device 10 canhave multiple possible combinations of spacing distances betweenmultiple light sources and detectors. Such a multiple light sourceand/or multiple detector implementation can allow increased flexibilityof the optical device 10. For example, since the depth of the implant 12may be application-specific, an optical device 10 having multiple lightsources and/or multiple detectors can be used for multiple applications.

The optical device 10 can be configured to ensure that substantiallyonly photons with wavelengths in the excitation wavelength range(s)reach the implant 12, and substantially only photons with wavelengths inthe emission wavelength ranges(s) reach at least one of the detectors16, 20. Such an arraignment can minimize photons from the light source18 reaching the detectors 16, 20, which can result in measurement error.

FIG. 2 is a schematic side view of an optical detection device formonitoring an implant, according to an embodiment. An array of lenses 22is aligned with an array of apertures 24 to restrict transmission ofoff-axis light to the detector 16. The lens arrays 22 and the aperturearray 24 are positioned with respect to the detector 16 to collectivelyrestrict the light emitted from the tissue that travels to the detector16 based on an input angle θ (also referred to herein as incident angle)of the emitted light relative to optical axes 30 of the apertures. Theoptical axes 30 of the apertures can be substantially perpendicular tothe surface of the detector 16. Each aperture from the array ofapertures 24 can be substantially aligned with a lens from the array oflenses 22. Similarly stated the optical axes 30 of the apertures can besubstantially coaxial with the center and/or axes of the lenses. Forexample, a substantially opaque portion of the array of apertures 24 canbe positioned below the edges of the lenses.

At least one layer of light control film 26 is arranged with the lensarray 22 and the aperture array 24. The light control film 26 canrestrict the light emitted from the tissue from entering the lens array22 and/or the aperture array 24 based on the incident angle of theemitted light relative to the film 26. In one example, the light controlfilm 26 is Vikuti™ optical grade micro-louver privacy film commerciallyavailable from 3M™, which can block light having an incident anglegreater than desired (e.g., greater than 24 degrees) relative to aperpendicular line through the film 26. This privacy film comprises aset of microlouvers that prevent light from large incident angles fromreaching the lens array 22. In other embodiments, the film 26 comprisesalternating transparent and opaque layers in an arrangement which issimilar to a Venetian blind. Light propagating from angles greater thana desired incident angle can be absorbed and/or reflected.

At least one filter 28 (e.g., a dichroic or dielectric filter) ispositioned to restrict transmission of light to the detector 16 towavelengths substantially within the desired emission wavelength range.Because the detection of optical signals is dominated by low levels ofreturn signals relative to the excitation light, the filter 28 canprevent scattered excitation light from blinding the detector 16.Suitable filters include band-pass, low-pass, and high pass filtersdepending upon the desired emission wavelength range for an application.Some modern optical filters have demonstrated 10⁻⁹ light rejection dueto improvements in coating technologies. Additionally, intermediatelayers of the optical detection system (e.g., the lens array 22, theaperture array 24, etc.) can include anti-reflective coatings to reduceor prevent light leaking through to the detector 16.

Due to fundamental properties of dichroic filters, maintaining a highlevel of light rejection requires careful design. One property ofdichroic filters that detracts from light rejection is the “blue shift”as a function of input angle, where the transmittance wavelengths ofdichroic filters change as a function of input angle. For the detectionlight emitted from the implant, there is a trade off between the inputangle and the absolute optical signal. The light leaving the tissue ishighly scattered and may form a lambertian distribution by the time itreaches the surface of the skin. The collection efficiency of theemitted light is proportional to ˜NA², where NA=Numerical Aperture=n sinθ, and θ is the input angle. To improve the collection efficiency, theallowable input angle θ can be increased without increasing the angle somuch to allow excitation light though the filter 28.

The lens array 22 and the aperture array 24 control the input angle θ oflight traveling to the detector 16. The lens array 22 and an aperturearray 24 restrict the light to an input angle less than θ, which in someembodiments is selected to be +/−20 degrees. The input angle θ can becontrolled by varying the size of the apertures and the focal length ofthe micro lenses in the lens array 22. The smaller the aperture, thenthe smaller is input angle θ. The longer the focal length, then thesmaller is input angle θ. Although not shown, a spacer can be used tomaintain separation between the surface of the aperture array 24 and thelens array 22.

FIG. 3 is a plan view of the aperture array 24 having a plurality ofapertures 25. In some embodiments, the aperture array 24 is constructedby patterning a metal mask on the surface of a silicon detector, such asthe detector 16 shown in FIG. 2. The lens array 22 may be fabricated asetched glass or molded plastic. In some embodiments, the lens array 22is a custom micro-lens array commercially available from JENOPTIKOptical Systems.

FIG. 4 is a schematic plan view of an optical detection device,according to an embodiment. The optical detection device of FIG. 4 isconfigured as a patch 32. At least one light source (not shown in FIG.4) and detector 38 are arranged in an optical reader, such that thepatch 32, that is configured to be placed on the skin. A light source isarranged to transmit the excitation light through a central via 34 inthe patch 32, and a single universal detector 38 substantially surroundsthe central via 34. In other embodiments, instead of the single detector38, a plurality of detectors can be used, for example, substantiallyencircling the central via 34 to detect the emitted light in a pluralityof emission wavelength ranges. In some embodiments, the opticaldetection device includes at least one light guiding component 36 in thecentral via 34. The light guiding component 36, such as a waveguide oroptical fiber, is arranged to guide the excitation light to the skin. Insome embodiments, a plurality of light sources (not shown for clarity inFIG. 4) are arranged to transmit the excitation light through thecentral via 34 (e.g., by means of one or more waveguides or opticalfibers) in a plurality of different excitation wavelength ranges.

As one possible example, one or more light sources may be arranged totransmit excitation light to the skin through the central via 34 havinga circular cross-section to transmit the excitation light through asubstantially circular surface area of the skin having a diameter ofabout 1 mm and a corresponding excitation surface area of about 0.8 mm².The detector 38 has a square cross-section and is positioned to detectlight emitted from a substantially square surface area of the skinthrough which the detected light passes as it travels to the detector38. The detection surface area is substantially square with sides of 10mm length, so that the total detection surface area is (10 mm×10 mm)−1mm²=99 mm². Accordingly, in this example, the ratio of detection surfacearea to excitation surface area is greater than 120:1.

FIG. 5 is a schematic exploded view of the patch 32. The patch 32includes multiple layers. Dimensions of the patch 32 may be, forexample, a diameter of about 16 mm and a thickness T of about 1.6 mm. Insome embodiments, the layers may include a plastic cover 40 having athickness of about 200 um, the light control film 26 having a thicknessof about 100 um, the filter 28 having a thickness of about 200 um, thelens array 22 having a thickness of about 100 um, and the aperture array24 patterned on a silicon detector layer 48 having a thickness of about200 um. The layers can also include a printed circuit board (PCB) 50having a thickness of about 400 um, a battery 52 having a thickness ofabout 300 um, and a case 54 having a thickness of about 200 um. The PCB50 can include one or more light sources. The PCB 50 can also includeprocessing electronics and/or a microprocessor in communication with oneor more detectors in the detector layer 48 to receive datarepresentative of the light detected in the emission wavelength rangeand programmed to determine at least one analyte value in dependenceupon the data. The central via 34 may be formed through a stack of thelayers (e.g., etched or drilled through the stack in the assemblyprocess).

FIG. 6 is a schematic side view of an optical detection device formonitoring an implant showing an arrangement of detection optics 60,according to an embodiment. In this embodiment, light emitted from theimplant and tissue in the emission wavelength range is transmittedthrough at least two layers of light control films 62, 64. The twolayers of light control films 62, 64 can restrict the light emitted fromthe tissue from entering the lens array 22 and/or the aperture array 24based on the incident angle of the emitted light relative to the films62, 64. In one example, the light control film 62 comprises alternatingtransparent and opaque layers in an arrangement which is similar to aVenetian blind. Light propagating from angles greater than a desiredincident angle is absorbed. The light control film 64 may includeVikuti™ optical grade micro-louver privacy film commercially availablefrom 3M™, which blocks light having an incident angle greater thandesired (e.g., greater than 24 degrees) relative to a perpendicular linethrough the film 64.

In some embodiments, the light control film 62 and/or 64 may be operableto restrict light emitted from the tissue from entering the lens array22 and the aperture array 24 based on a combination of incident angleand azimuth. For example, in an embodiment where the light control film62 and/or 64 includes multiple micro-louvers, the light control film 62and/or 64 may be effective at blocking high angle-of-incidence lighthaving an azimuth substantially perpendicular to the micro-louvers, butmay be relatively ineffective at blocking high angle-of-incidence lighthaving an azimuth substantially parallel to the micro-louvers. In somesuch embodiments, two layers of light control film 62, 64 can becross-hatched or otherwise disposed such that louvers or other lightcontrol elements are non-parallel such that the light control film 62,64 are collectively effective at blocking high angle-of-incidence lighthaving different azimuths.

In some embodiments, the films 62, 64 may be substantially the same aseach other, or comprises different types of privacy film. Additionally,the filter 28 (e.g., a dichroic or dielectric filter) may be positionedbetween the aperture array 24 and the detector 16 to restrict thetransmission of the emitted light to the detector 16 to wavelengthssubstantially within the emission wavelength range(s). The operation ofthe embodiment of FIG. 6 can be similar to the operation of theembodiment of FIGS. 1-2 previously described.

FIG. 7 is a schematic side view of an optical detection device formonitoring an implant. An array of lenses 122 is aligned with an arrayof apertures 24 to restrict the transmission of off-axis light to thedetector 16. The lens arrays 122 and the aperture array 24 arepositioned with respect to the detector 16 to restrict the light emittedfrom the tissue that travels to the detector 16 according to an inputangle θ of the emitted light relative to optical axis 30 of theapertures. The optical axis 30 of the apertures can be substantiallyperpendicular to the surface of the detector 16.

The lens array 122 includes light-blocking elements 72. Thelight-blocking elements 72 can be disposed between the apertures 25 toblock propagation of off-axis light rays 74, 76 through the apertures25. The light-blocking elements 72 can include black resin, metal,and/or metal film deposited in cavities of a substrate 123 of the lensarray 122 positioned. At least one filter 28 is positioned to restrictthe transmission of the emitted light to the detector 16 to wavelengthssubstantially within the emission wavelength range. Optionally, one ormore layers of light control film may be included in this embodiment.The operation of the embodiment of FIG. 7 can be similar to theoperation of the embodiment of FIGS. 1-2 previously described.

FIGS. 8A-8D depict a lens array 122 with light-blocking elements invarious stages of fabrication, according to an embodiment. FIG. 8A showsa side view of the lens array 122 which may be fabricated as etchedglass or molded plastic. In some embodiments, the lens array 122 is amicro-lens array commercially available from JENOPTIK Optical Systems.FIG. 8B shows cavities 78 which can be, for example, etched orintegrally molded into a substrate portion 123 of the lens array 122. Asshown in FIG. 8C, the cavities 78 can be filled with a substantiallyopaque material to form light-blocking elements 72. The light-blockingelements 72 can be constructed of, for example, black resin, metal,and/or metal film. As shown in FIG. 8D, the aperture array 24 may bepositioned adjacent to the lens array 122 (with a spacer in someembodiments) such that light-blocking elements 72 are positioned betweenthe apertures 25. In some embodiments, the aperture array 24 isconstructed by patterning a metal mask on the surface of a silicondetector and positioning the detector with aperture array 24 adjacent tothe lens array 22 with light-blocking elements 72 such that thelight-blocking elements 72 are positioned between the between apertures25.

FIG. 9 is a schematic plan view of an optical detection device 210,according to an embodiment. The optical detection device 210 includesfour detectors 216, 220, 222, and 224 and a light source 218. Theoptical detection device 210 has a relatively large ration of detectorsurface area to light source surface area (also referred to herein as“surface area ratio”). The large surface area ratio can improvedetection of implant signals, when the implant is embedded insubcutaneous tissue (e.g., 1-4 mm under the surface of the skin). Inparticular, the light source 218 and four detectors 216, 220, 222, 224are arranged such that the ratio of the surface area of the skin throughwhich the detected light passes as it travels to the detectors 216, 220,222, 224 to the surface area of the skin through which the excitationlight is transmitted is at least 4:1. For example, in one embodiment thelight source 218 has a circular cross-section and is positioned totransmit the excitation light through a substantially circular surfacearea of the skin having a diameter of about 3 mm, a radius of about 1.5mm, and an excitation surface area of about 7 mm². The four detectors216, 220, 222, 224 have square cross-sections and are positioned todetect light emitted from four substantially square surface areas of theskin, through which the detected light passes as it travels to thedetectors. Each of the four detection surface areas is substantiallysquare with sides of 3 mm, so that the total detection surface area is4×9 mm²=36 mm². Accordingly, in this example, the ratio of detectionsurface area to excitation surface area is slightly greater than 5:1.

In some embodiments, the optical detection device 210 can be configuredto detect implant signals at a lateral distance at least twice the depthof the implant. For example, at least a portion of at least one of thedetectors 216, 220, 222, 224 can be at least twice as far away from theimplant laterally as that portion is from the implant distally. Forexample, in an instance where the light source 218 is centered over animplant that is embedded under 4 mm of tissue, at least a portion of atleast one of the detectors 216, 220, 222, 224 can be 8 mm away from thecenter of the light source 218. Similarly stated, the furthermost edgeor corner of at least one of the detectors 216, 220, 222, 224 can be atleast twice as far away from the center of the light source 218 as theimplant is deep. In an alternate embodiment, such as an embodimenthaving a single or universal detector, the detector can have a radius atleast twice the depth of the implant. In other embodiments, the opticaldetection device 210 can be configured to detect implant signals at alateral distance at least three times, at least five times, or any othersuitable multiple of the depth of the implant. An optical detectordevice 210 operable to detect implant signals a relatively large lateraldistance from the implant may be able to detect a larger portion of anemitted signal, particularly in a high-scattering environment. Capturinga larger portion of the emitted signal can improve detection accuracy.

FIG. 10 is a schematic plan view of an optical detection device 310,according to an embodiment. As compared to the optical detection device210, in this embodiment, the four detectors 316, 320, 322, 324 arepositioned closer to the light source 318 as they surround or encirclethe light source 318, and the ratio of detection surface area toexcitation surface area is larger. For example, the light source 318 mayhave a circular cross-section and is arranged to transmit the excitationlight through a substantially circular surface area of the skin having adiameter of about 2 mm, a radius of about 1 mm, and an excitationsurface area of about 3.14 mm². The four detectors 316, 320, 322, 324have square cross-sections and are positioned to detect light emittedfrom four substantially square surface areas of the skin, through whichthe detected light passes as it travels to the detectors. Each of thefour detection surface areas is substantially square with sides of 6 mm,so that the total detection surface area is 4×36 mm²=144 mm².Accordingly, in this example, the ratio of detection surface area toexcitation surface area is slightly greater than 45:1.

FIG. 11 is a schematic, plan view of aspects of an optical detectiondevice 410, according to another embodiment. In this embodiment, fivecircular-shaped detectors 428A, 428B, 428C, 428D, and 428E surround orencircle a central via 434. The central via 434 may be a hole in thedevice 410. A plurality of light sources 426 are arranged to transmitexcitation light in a plurality of different wavelength ranges throughthe central via 434. As one possible example, the light sources 426 maybe arranged to transmit excitation light to the skin through the centralvia 434 having a circular cross-section to transmit the excitation lightthrough a substantially circular surface area of the skin having adiameter of about 3 mm and a corresponding excitation surface area ofabout 7 mm². The five detectors 428A, 428B, 428C, 428D, and 428E havecircular cross-sections and are positioned to detect light emitted fromfive substantially circular surface areas of the skin, through which thedetected light passes as it travels to the detectors. Each of the fivedetection surface areas is substantially circular with a diameter of 5mm, so that the total detection surface area is 5×19.6 mm²=98 mm².Accordingly, in this example, the ratio of detection surface area toexcitation surface area is slightly greater than 13:1.

It will be clear to one skilled in the art that the above embodimentsmay be altered in many ways without departing from the scope of theinvention. For example, many different permutations or arrangements ofone or more light sources, one or more detectors, filters, and/or lightguiding elements connecting the optical components may be used torealize the device and method of the invention. For example, alternativeembodiments may have different dimensions and/or wavelengths.Embodiments may include cabled or wireless hand-held readers, wirelessskin patch readers, bench-top instruments, imaging systems, smartphoneattachments and applications, or any other configuration that utilizesthe disclosed optics and algorithms.

In some embodiments described herein, a monitoring device can beoperable to simultaneously emit an excitation optical signal and detectan emission signal. For example, the detector of such a monitoringdevice can be shielded from reflected or back-scattering excitationlight using apertures, light-blocking elements, filters, light controlfilm, etc. In other embodiments, a monitoring device can be operable toemit an excitation optical signal during one period of time, and detectan emission signal during another period of time in which the excitationoptical signal is deactivated.

Tissue optical heterogeneity in some cases may be significant. Thus, itmay be advantageous to utilize a single light source and a singledetector to assure that every color passes through the same opticalpathway through the tissue. In one embodiment, a light source can bepositioned with a set of moveable filters between the light source andthe surface of the skin. Similarly a single photodetector can beutilized in place of separate discrete detector elements. The detectormay be used to detect different wavelength ranges by using moveable orchangeable filters to enable multiple wavelengths to be measured.Changing or moving filters may be accomplished by a mechanical actuatorcontrolling a rotating disc, filter strip or other means. Alternatively,optical filters may be coated with a material that, when subjected tocurrent, potential, temperature or another controllable influence,changes optical filtering properties, so that a single photodetector canserve to detect multiple wavelength ranges.

In some embodiments, the devices and methods of the present inventionmake use of wafer-based micro-optics. These systems are createdlithographically, but can be replicated at low cost. The technologyallows for layers of optics and detectors to be bonded at the waferlevel and then diced into individual detector systems. Suitablecomponents include etched refractive lenses, polymer replicatedrefractive lenses, etched binary lenses, replicated binary lenses,replicated holograms, and replicated volume holograms.

In some embodiments, a complementary metal-oxide-semiconductor (CMOS)detector may be used as an integral part of the optical system. Theadvantage of a CMOS sensor is the ability to integrate the detection,excitation, and digital filtering circuitry into a single piece ofsilicon. A new technology was recently announced, sCMOS, whereresearchers have been able to greatly reduce the noise in CMOS detectorsto be comparable to charge charge-coupled device (CCD) detectors.Another benefit to a CMOS integrated solution is the ability to performlock-in detection and digital filtering on the signals to reduce oreliminate the impact of ambient light.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, notlimitation, and various changes in form and details may be made. Anyportion of the apparatus and/or methods described herein may be combinedin any combination, except mutually exclusive combinations. Theembodiments described herein can include various combinations and/orsub-combinations of the functions, components and/or features of thedifferent embodiments described.

What is claimed is:
 1. An apparatus, comprising: a planar base; a lightsource coupled to the planar base and configured to transmit anexcitation optical signal through a first surface area of skin to animplanted sensor; one or more detectors coupled to the planar base andconfigured to detect an analyte-dependent optical signal emitted fromthe implanted sensor through a second surface area of skin in responseto the implanted sensor being illuminated by the excitation opticalsignal, the second surface area of the skin being at least four timesthe first surface area of the skin; a first lens from an array oflenses, the first lens configured to focus at least a portion of theanalyte-dependent optical signal onto at least one of the one or moredetectors, the first lens defining a first lens axis; and a second lensfrom the array of lenses, the second lens configured to focus at least aportion of the analyte-dependent optical signal onto at least one of theone or more detectors, the second lens defining a second lens axissubstantially parallel to and non-coaxial with the first lens axis. 2.The apparatus of claim 1, further comprising: an aperture, the aperture,the first lens, and at least one of the one or more detectorscollectively configured to inhibit a photon having an angle of incidencegreater than a predetermined angle of incidence from striking thatdetector.
 3. The apparatus of claim 1, wherein the array of lenses is amonolithically formed array of lenses.
 4. The apparatus of claim 1,further comprising: an array of apertures, each aperture from the arrayof apertures being substantially aligned with a center of a lens fromthe array of lenses.
 5. The apparatus of claim 1, further comprising: afilter configured to attenuate optical signals having wavelengthsassociated with the light source.
 6. The apparatus of claim 1, furthercomprising: a filter configured to attenuate optical signals havingwavelengths associated with the light source, the filter configured totransmit the analyte-dependent optical signal with substantially noattenuation.
 7. The apparatus of claim 1, further comprising: a dichroicfilter configured to attenuate optical signals having wavelengthsassociated with the light source, the dichroic filter configured to blueshift analyte-dependent optical signals towards the wavelengthassociated with the light source as a function of an angle of incidence,the one or more detectors not being configured to detect a blue-shiftedanalyte-dependent optical signal.
 8. The apparatus of claim 7, wherein aportion of the excitation optical signal is scattered by tissuesurrounding the implant, the apparatus further comprising: an aperture,(1) the aperture, (2) the array of lenses, and (3) the dichroic filterare collectively configured to inhibit the portion of the excitationoptical signal from entering the at least one of the one or moredetectors.
 9. A system including the apparatus of claim 1, the systemfurther comprising: the implanted sensor configured to be disposed adepth beneath the skin, at least a portion of the detector spaced alateral distance from the light source, the lateral distance being atleast twice the depth.
 10. A system including the apparatus of claim 1,the system further comprising: the implanted sensor configured to beimplanted in a body at a depth, the light source disposed directly abovethe implanted sensor, at least a portion of the detector a distance fromthe light source that is at least twice the depth.
 11. The apparatus ofclaim 1, wherein the one or more detectors define an opening, the lightsource configured to transmit the excitation optical signal to theimplanted sensor through the opening.
 12. The apparatus of claim 1,wherein: the one or more detectors include a plurality of detectors; andthe planar base defines an opening, the light source configured totransmit the excitation optical signal to the implanted sensor throughthe opening, the plurality of detectors coupled to the planar base andsubstantially surrounding the opening.
 13. An apparatus, comprising: alight source configured to transmit an excitation optical signal to asensor implanted at a depth of at least 1 mm under a surface of a skin;a detector configured to detect an analyte-dependent optical signalemitted from the sensor in response to the sensor being illuminated bythe excitation optical signal, at least a portion of the detector spacedat least 2 mm from the light source such that at least the portion ofthe detector is spaced apart from the light source at least twice thedepth of the sensor; a cover configured to be disposed between thedetector and the skin, the detector being less than 2 mm from the cover;and a monolithically formed array of lenses disposed between the coverand the detector, a lens from the monolithically formed array of lensesconfigured to focus a portion of the analyte-dependent optical signalonto the detector.
 14. The apparatus of claim 13, further comprising: anaperture configured to inhibit a photon having an angle of incidencegreater than a predetermined angle of incidence from striking thedetector.
 15. The apparatus of claim 13, wherein the monolithicallyformed array of lenses includes a first lens defining a first lens axisand a second lens defining a second lens axis substantially parallel toand non-coaxial with the first lens axis.
 16. The apparatus of claim 13,further comprising: an array of apertures, each aperture from the arrayof apertures being substantially aligned with a center of a lens fromthe monolithically formed array of lenses.
 17. The apparatus of claim13, further comprising: a filter configured to attenuate optical signalshaving wavelengths associated with the light source.
 18. The apparatusof claim 13, further comprising: a filter configured to attenuateoptical signals having wavelengths associated with the light source, thefilter configured to transmit the analyte-dependent optical signal withsubstantially no attenuation.
 19. The apparatus of claim 13, furthercomprising: a dichroic filter configured to attenuate optical signalshaving wavelengths associated with the light source, the dichroic filterconfigured to blue shift analyte-dependent optical signals towards thewavelength associated with the light source as a function of an angle ofincidence, the detector not being configured to detect a blue-shiftedanalyte-dependent optical signal.
 20. The apparatus of claim 13, whereina portion of the excitation optical signal is scattered by tissuesurrounding the implant, the apparatus further comprising: an aperture,(1) the aperture, (2) the monolithically formed array of lenses, and (3)the dichroic filter are collectively configured to inhibit the portionof the excitation optical signal from entering the detector.
 21. Theapparatus of claim 13, wherein: the light source is configured to bedisposed directly above the sensor.
 22. The apparatus of claim 13,wherein the light source is configured to transmit the excitationoptical signal through an opening having a first cross-sectional area,and the detector has a second cross-sectional area, the secondcross-sectional area being at least four times the first cross-sectionalarea.
 23. The apparatus of claim 13, wherein the detector defines anopening, the light source configured to transmit the excitation opticalsignal to the sensor through the opening.
 24. The apparatus of claim 13,wherein the detector is one of a plurality of detectors, the apparatusfurther comprising: a base defining an opening, the light sourceconfigured to transmit the excitation optical signal to the sensorthrough the opening, the plurality of detectors coupled to the base andsubstantially surrounding the opening.
 25. An apparatus, comprising: alight source configured to transmit an excitation optical signal to animplanted sensor; a base defining an opening, the light sourceconfigured to transmit the excitation optical signal to the implantedsensor through the opening; one or more detectors coupled to the baseand configured to detect an analyte-dependent optical signal emittedfrom the implanted sensor in response to the implanted sensor beingilluminated by the excitation optical signal; a first lens from an arrayof lenses, the first lens configured to focus at least a portion of theanalyte-dependent optical signal onto the at least one of the one ormore detectors, the first lens defining a first lens axis; and a secondlens from the array of lenses, the second lens configured to focus atleast a portion of the analyte-dependent optical signal onto at leastone of the one or more detectors, the second lens defining a second lensaxis substantially parallel to and non-coaxial with the first lens axis.26. The apparatus of claim 25, wherein the one or more detectors includeplurality of detectors coupled to the base and substantially surroundingthe opening.
 27. The apparatus of claim 25, wherein the base is aprinted circuit board.